In the largest twin study to date of Sz and BVs (n
= 684 individuals) we examined the relative contributions of genetic and environmental influences on the association of BVs and Sz. In an international multicenter collaboration we pooled data from four research centers, creating a uniquely powered twin cohort. We found a small but significant association between Sz and a smaller cerebral volume, of which 77% can be explained by genetic factors that influence both the lower cerebral volume and (the risk for developing) Sz. Lower cerebral white matter volume as well as larger third ventricular volume also showed a significant association with the liability for Sz, which was largely explained by genetic factors. These accounted for significant portions of the phenotypic correlations (94% and 83%, respectively), indicating that smaller cerebral (white) matter and larger third ventricle are related to the genetic risk to develop Sz. Thus, our results suggest that the smaller total cerebral volume and particularly that of white matter and larger third ventricle volume is linked to Sz, mainly through genetic factors that are associated to the disorder. In contrast, a significant environmental correlation for cerebral gray matter (−.36; 95% CI: −.55 to −.15) and cortical frontal gray matter (−.54; 95% CI: −.74 to −.29) was found, without a significant phenotypic association between smaller cerebral or cortical frontal and occipital gray matter volume and liability to Sz. Interestingly, there are contrasting contributions (although not significant) of genetic and common environmental factors. In other words, a negative association was found between genetic factors and lower volume, whereas common environmental factors showed a positive association with larger gray matter volume. This is in line with a recent study in MZ twins concordant and discordant for Sz showing a heterogeneous pattern of prefrontal volume reduction in twins with Sz. Medial and orbital frontal cortex showed significant volumetric reductions in twins with Sz only if they were concordant but not discordant for the disorder, relative to control subjects. In contrast, inferior frontal cortex showed no statistically significant differences across groups, whereas superior frontal cortex was reduced in Sz patients, regardless of their concordance status (41
That impaired brain development is important in the pathogenesis of Sz is not new (42,43
). Evidence from both genetic and epidemiological studies that aberrant neurodevelopment is crucial in the risk for Sz is mounting. Association studies have identified common risk variants that are associated with Sz (e.g., neuregulin, dysbindin, Disrupted in Schizophrenia 1 [DISC1]). In addition, small structural changes (copy number variants) in the genome seem causative of Sz. Interestingly, these genes as well as the copy number variants seem to influence neurodevelopment, cell signaling, and synaptic functions (44
). Moreover, Fatemi and Folom (45
) imply that Neuregulin-I and DISC1 not only play a key role in brain development but are likely to be functionally convergent.
Epidemiological data show that deficits and delays in cognitive development (46–48
), emotional problems, interpersonal difficulties, and impairments in neuromotor and receptive language (48
) are present during childhood and adolescence in individuals who will later go on to develop Sz. Crucially, the risk for Sz is increased in those with a lower IQ score, in particular in the presence of impaired nonverbal reasoning (49
). Furthermore, recent work has shown that there are significant common genetic influences acting on the covariance between IQ, schizotypy, abnormal social functioning, and schizophrenia (50
). This suggests that the same genetic factors that impair intelligence, increase schizotypy, impede social development, and decrease BV in childhood also determine the liability to Sz (39,50
Although we found a significant association between Sz and smaller cerebral volume, the correlation is relatively low, rph
= −.22. This subtle effect might not be surprising, because it was not expected that the risk for Sz explains a large part of the variance in cerebral volume. A correlation of −.22 indicates that susceptibility for Sz explains 4.8% of the variance, which is small but by no means negligible. This is even lower for white matter volume (−.17). Importantly, our results show that this effect in cerebrum and cerebral white matter is largely (77% and 94%, respectively) explained by shared genetic rather than environmental or disease-related factors. The genetic contribution to association between white matter volume and Sz liability has been suggested previously with a classic repeated measures General Linear Model analyses in the Utrecht discordant twin sample (51
). Of note, these data are also part of the current pooled sample.
Our findings must be viewed in light of several methodological limitations. First, this pooled twin sample is not a population-based sample of twins with Sz and healthy control twins from the United Kingdom, The Netherlands, and Germany, except for the twin sample from Helsinki. Second, this study found no significant shared environment contribution to the variation in BVs, which rules it out as a possible source of overlap with the disorder. However, by constraining the BV familial environmental paths to zero in the AE model for some volumes, its effects (even if very small) will automatically be apportioned to the genetic component, therefore inflating the genetic correlation between BV and disorder. Third, we cannot distinguish how much each site contributes to the explained variation in BV due to A or E. Fourth, in the present study we cannot account for biological gene × environment interaction effects, because in the classical twin model the effects of interaction and correlation between latent A, C, and E factors is assumed to be zero. Twin data on their own cannot resolve these issues. There are (rather complex) designs that enable ways of testing these effects (52
), but that is beyond the scope of most twin studies.
Finally, the findings of our study are limited to global BV measures. The advantage of global BVs is their robustness and stability in measurements, as is indicated by the relatively high ICCs we found across sites. In contrast, the reliability of voxel-based and cortical thickness measurements seem to differ between brain areas (53
). We can make no anatomically specific inferences about the location of the focal gray and white matter deficits and how they might be differently related to the genetic and environmental risk to develop Sz. Future studies should deploy more focally sensitive approaches to brain anatomy with voxel-based morphometry or cortical thickness measurements. In addition, associations with other candidate endophenotypic markers such as intellectual functioning (IQ) need to be investigated.
In conclusion, we found that genetic factors largely explain the modest but significant association between Sz and total cerebral and white matter volume decrease and increase in third ventricle volume. These findings indicate that some of the genes that increase the risk to develop Sz are likely to be involved in crucial neurodevelopmental processes in the brain. Thus, evidence from genetic, epidemiological, and—as indicated by the current results—neuroimaging studies seem to converge on the fact that the risk to develop Sz is the consequence of genetically mediated aberrant neurodevelopment.